Lecture 21

Question 1

Congenital insensitivity to pain

Answer 1

you don’t feel pain due to mutation of TrkA (receptor tyrosine kinase for NGF) which affects pain receptors

Question 2

Functions of pain

Answer 2

• helps us to avoid damage
• teaches us to avoid harmful situations
• encourages us to rest injured body

Question 3

what is nociception

Answer 3

physiological response to real, or potential tissue damage

Question 4

what is pain

Answer 4

unpleasant sensory or emotional experience associated with real or potential tissue damage

Question 5

tissue damage without pain (difference between nociception and pain)

Answer 5

• reduced pain in presence of noxious stimulants
• e.g. hypnosis or placebo

Question 6

nociception physiological mechanisms

Answer 6

nociceptors are ion channels at the end of free nerve endings in the skin

Question 7

types of nociceptive afferent

Answer 7

• A delta (thin myelination)
• C fibre (no myelination)

Question 8

properties of nocicetive afferents

Answer 8

• thermal (noxious) (burn)
• mechanosensitive (high threshold) (bang hand with hammer)
• polymodal (both)

Question 9

nociceptive responses in trigeminal ganglion

Answer 9

• use calcium imaging to detect activity of ganglion
• used 2 stimulus: heat, hair pull
• cells are almost always exclusive to thermal or mechanosensitive but can identify some polymodal cells

Question 10

noxious mechanical stimulus

Answer 10

e.g. step in a pin
1. activates high threshold mechanoreceptors that respond by opening ion channels in nociceptors so positive ions flow into cell and activate it
2. you then get an inflammatory response due to ‘tissue damage’. Various immune cells bind to receptors on nociceptor membrane to amplify response (e.g. prostoglandn, ATP, H+)

Question 11

noxious heat stimulus

Answer 11

e.g. touch hot oven
1. Transient receptor potential (TRP) ion channels open at >45degC
results in influx of sodium and calcium leads to receptor potential

Question 12

what TRP channels are involved in noxious heat response

Answer 12

TRPV1 ( TRPM3, TRPA1 )

Question 13

TRP receptors

Answer 13

activated by heat and molecule called Capsaicin - component in chilli peppers - which binds to receptors in mouth to activate them

• underlie heat pain

Question 14

how do nociceptive signals reach the CNS ?

Answer 14

• nociceptor cell bodies in dorsal root ganglion just outside of the spinal cord

Question 15

A-delta and C central axon branches enter spinal cord

Answer 15

• synapse in dorsal horn
• laminae I, II & V
• no collaterals direct to brain stem all go through spinal cord (vs. touch does have collateral)

Question 16

anterolateral pathways: spinothalamic and spinoreticular tracts

Answer 16

axons that convey nociception to brain stem

Question 17

spinothalamic tract

Answer 17

originates in layers I and V of spinal cord and projects to thalamus, where it terminates

Question 18

nociceptive projection

Answer 18

projects to thalamus but also many other parts of the brain as lots of places may need to know about tissue injury, but most important we focus on spinothalamic tract

Question 19

where does spinothalamic tract terminate in the thalamus

Answer 19

• ventroposterior nucleus (to cortex) (same as touch)
• ventromedian nucleus
• intralaminar nuclei (central lateral, mediodorsal)

Question 20

ventroposterior nucleus

Answer 20

projects to
- somatosensory cortex
- insula
- anterior cingulate

Question 21

summary

Answer 21

• touch signals and nociceptive signals are conveyed by distinct ascending pathways through NS
• Nociceptive signals are widely distributed within the CNS

Question 22

2 types of sensitisation and the 2 mechanisms

Answer 22

• hyperalgesia
• allodynia
• peripheral sensitization
• central sensitization

Question 23

allodynia

Answer 23

pain in response to non-noxious stimulus
e.g. walking on a sprained ankle

Question 24

Peripheral sensitization

Answer 24

• hyperalgesia and allodynia
• inflammatory response
• prostaglandin produced binds to membrane of nociceptors and amplifies response

Question 25

Aspirin & Ibuprofen

Answer 25

- COX inhibitors - block prostaglandin synthesis - reduces effect of response

Question 26

central sensitisation

Answer 26

- allodynia -increase in excitability of second order neurons in dorsal horn of spinal cord - COX enzyme involved in this mechanism, increased transcription in dorsal horn, increased prostaglandin production, increased dorsal horn activity - second site of COX inhibitors

Question 27

COX

Answer 27

cyclooxygenase

Question 28

endogenous analgesia

Answer 28

mediated by endogenous analgesia system - how the brain controls pain 'relief'

Question 29

Sprenger et al 2012 - endogenous system

Answer 29

- noxious stimulants e.g. heat on arm at ~48degC - causes pain but no tissue damage - n-back task: easy or hard - distractor task from pain - pain rating was significantly higher for less demanding (1-back) task (compared to 2-back)

Question 30

periaqueductal gray (PAG)

Answer 30

- at brainstem this surrounds the aquaduct (gray for cell bodies/neurons) - electrical stimulation of PAG blocks pain response - produces analgesia - important in endogenous analgesia system

Question 31

endogenous analgesia system

Answer 31

PAG -> Raphe nuclei -> spinal cord (dorsal horn) (which is conected to C fibre) - so when PAG activated reduces activity in C fiber... and therefore reduce dorsal horn neural activity

Question 32

Sprenger et al 2012 spinal cord for endogenous system

Answer 32

-fMRI of spinal cord - measure response to noxious stimuli - response in dorsal horn reduced in 2 back condition...

Question 33

opioids + PAG

Answer 33

- morphine derivatives are powerful analgesics - opiate sensitive neurons in PAG and spinal cord - injection opiate anatgonist into PAG blocks opiate analgesia

Question 34

opiate antagonist

Answer 34

naloxone

Question 35

opiates + analgesia

Answer 35

- naloxone vs NaCl control - significant reduction of analgesic effect in 2-back condition - yes distraction effect depends on opiate mechanisms in the spinal cord... they must be involved in endogenous analgesia

Question 36

summary

Answer 36

brain has ability to control the degree to which tissue damage translates into pain - this is endogenous analgesia - key neural structure is PAG - PAG is site of action of (endogenous) opiates